Glioblastoma multiforme (GBM) or glioblastoma, is the most common and aggressive malignant primary brain tumor in humans. An effective treatment that increases patient survival would represent a significant advance in the field, and provide a desperately needed new therapy for this deadly disease. EnduRx is focused on the development of new, targeted systems for cancer treatment. Our collaborators, at the Sanford-Burnham Medical Research Institute (SBMRI), led by Prof. Ruoslahti, have developed an exciting new tumor targeted nanosystem for cancer therapy. This nanosystem has shown unprecedented anti- cancer activity in highly drug resistant/refractory mouse models of glioblastoma, which closely mimic the human disease. We have identified new homing peptides that can carry nanoparticles deep into the target tissue. Phase I of this application will test whether these new tissue penetrating, homing peptides can improve the efficacy of the nanosystem. Support of this Fast-Track SBIR application will enable selection of a preclinical candidate and accelerate the development of a new therapeutic for GBM and other cancers, via the following aims: Phase I: Optimization of CGKRK-D(KLAKLAK)2-NWs Aim 1. Synthesis of CGKRK-(homing peptide)-D(KLAKLAK)2-NW analogues. Aim 2. Assay new constructs to confirm p32-binding and cell and tissue penetration The most promising p32 homing peptide-D(KLAKLAK)2-NW analogue identified in Phase I will advance into further development in Phase II. Phase II: In vivo efficacy studies, product development and pilot toxicology Aim 1. In vivo pharmacology Aim 2. Synthesis and analysis of candidate p32-homing peptide-D(KLAKLAK)2-NWs Aim 3. Pharmacokinetic studies and second species selection for safety Aim 4. Dose-escalating toxicology in rodents: determine dose range for toxicology studies At the end of Phase II, a clinical development candidate will have been identified that is ready to enter GLP toxicology studies, in support of an IND submission for development of a new, safe and effective treatment for cancer. In addition, the iron oxide component serves as a MRI contrast agent for diagnostic imaging.